Investigation of neuropathology of synucleinopathies using novel model mice.

• Project/Area Number: 21700399
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: 財団法人東京都医学総合研究所 (2011); Tokyo Metropolitan Organization for Medical Research (2009-2010)
• Principal Investigator: FUJITA Masayo 財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主席研究員 (90415539)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経変性疾患 / シヌクレイン / シヌクレイノパチー / 神経変性 / トランスジェニックマウス

Research Abstract

To establish useful model animal of Parkinson's Disease(PD) and dementia with Lewy bodies(DLB), transgenic(Tg) mice overexpressing dementia with Lewy bodies(DLB)-linkedβsyn(P123H) were made and analyzedβsyn(P123H) Tg mice mainly showed non-motor symptoms, whereas mice overexpressingβsyn(P123H)/αsyn were characterized by extensive phenotypes, including neuronal cell death. These mice model could be a powerful tool with which to investigate the pathogenic mechanism of PD and DLB.

Research Products

• [Journal Article] Ibuprofen ameliorates protein aggregation and astrocytic gliosis, but not cognitive dysfunction, in a transgenic mouse expressing dementia with Lewy bodies-linked P123H b-synuclein (2012)
  • Author(s): S ekiyama K, Fujita M, Sekigawa A, Takamatsu Y, Waragai M, Takenouchi T, Sugama S, Hashimoto M
  • Journal Title: Neurosci Lett Volume: 515(1) Issue: 1 Pages: 97-101
  • DOI: 10.1016/j.neulet.2012.03.037
  • Peer Reviewed
• [Journal Article] The activation of P2X7 receptor induces cathepsin D-dependent production of a 20-kDa form of IL-1b under acidic extracellular pH in LPS-primed microglial cells (2011)
  • Author(s): T akenouchi T, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Sekigawa A, Sekiyama K, Sato M, Kojima S, Conti B, Hashimoto M, Kitani H
  • Journal Title: J. Neurochem Volume: 117 Pages: 712-723
  • DOI: 10.1111/j.1471-4159.2011.07240.x
  • Peer Reviewed
• [Journal Article] Cold stress induced morphological microglial activation and increased IL-1βexpression in astroglial cells in rat brain (2011)
  • Author(s): Sugama S, Takenouchi T, Fujita M, Kitani H, Hashimoto M
  • Journal Title: J. Neuroimmunol Volume: 233 Issue: 1-2 Pages: 29-36
  • DOI: 10.1016/j.jneuroim.2010.11.002
  • Peer Reviewed
• [Journal Article] Aβ-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain (2010)
  • Author(s): Fujita M, Sugama S, Sekiyama K, Sekigawa A, Tsukui T, Nakai M, Waragai M, Takenouchi T, Takamatsu Y, Wei J, Rochenstein E, Laspada AR, Masliah E, Inoue S, Hashimoto M
  • Journal Title: Nat Commun Volume: 1 Issue: 1 Pages: 110-110
  • DOI: 10.1038/ncomms1101
  • Peer Reviewed
• [Journal Article] A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain. (2010)
  • Author(s): Fujita M
  • Journal Title: Nat.Commun. Volume: 1 Pages: 110-110
  • Peer Reviewed
• [Journal Article] Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells (2009)
  • Author(s): Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P
  • Journal Title: Int. J. Biochem. Cell Biol Volume: 41 Issue: 10 Pages: 2015-2024
  • DOI: 10.1016/j.biocel.2009.05.008
  • Peer Reviewed
• [Journal Article] Protective role of endogeneous gangliosides for lysosomal pathology in a cellular model of synuclenopathies (2009)
  • Author(s): Wei J, Fujita M, Nakai M, Waragai M, Sekigawa A, Sugama S, Takenouchi T, Masliah E, Hashimoto M
  • Journal Title: Am. J. Pathol Volume: 174(5) Issue: 5 Pages: 1891-909
  • DOI: 10.2353/ajpath.2009.080680
  • Peer Reviewed
• [Journal Article] The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells (2009)
  • Author(s): Takenouch T, Nakai M, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Wei J, Sekigawa A, Sato M, Kojima S, Kitani H, Hashimoto M
  • Journal Title: J Immunol Volume: 182 Issue: 4 Pages: 2051-2062
  • DOI: 10.4049/jimmunol.0802577
  • Peer Reviewed
• [Journal Article] Microglial activation is inhibited by corticosterone in dopaminergic neurodegeneration (2009)
  • Author(s): Sugama S, Takenouchi T, Kitani H, Fujita M, Hashimoto M
  • Journal Title: J. Neuroimmunol Volume: 208(1-2) Issue: 1-2 Pages: 104-114
  • DOI: 10.1016/j.jneuroim.2009.01.016
  • Peer Reviewed
• [Journal Article] Differential microglial activation between acute stress and lipopolysaccharide administration (2009)
  • Author(s): Sugama S, Takenouchi T, Conti B, Hashimoto M
  • Journal Title: J. Neuroimmunol Volume: 207(1-2) Issue: 1-2 Pages: 24-31
  • DOI: 10.1016/j.jneuroim.2008.11.007
  • Peer Reviewed
• [Journal Article] Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. (2009)
  • Author(s): Parihar MS
  • Journal Title: Int.J.Biochem.Cell Biol. 41 Pages: 2015-2024
  • Peer Reviewed
• [Journal Article] Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. (2009)
  • Author(s): Wei J
  • Journal Title: Am.J.Pathol. 174 Pages: 1891-1909
  • Peer Reviewed
• [Journal Article] The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. (2009)
  • Author(s): Takenouch T
  • Journal Title: J Immunol. 182 Pages: 2051-2062
  • Peer Reviewed
• [Journal Article] Microglial activation is inhibited by corticosterone in dopaminergic neurodegeneration. (2009)
  • Author(s): Sugama S
  • Journal Title: J.Neuroimmunol. 208 Pages: 104-114
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Sugama S
  • Journal Title: J.Neuroimmunol. 207 Pages: 24-31
  • Peer Reviewed
• [Journal Article] Cold stress induced morphological microglial activation and increased IL-1β expression in astroglial cells in rat brain.
  • Author(s): Sugama S
  • Journal Title: J Neuroimmunol. Volume: (In press)
  • Peer Reviewed
• [Presentation] Aβ-synuclein mutation linked to familial dementia with Lewy bodies produces neurodegeneration when expressed in mouse brain (2011)
  • Author(s): Fujita M., et al.
  • Organizer: ADPD 2011
  • Place of Presentation: バルセロナ、スペイン
• [Presentation] A β-synuclein mutation linked to familial dementia with Lewy bodies produces neurodegeneration when expressed in mouse brain. (2011)
  • Author(s): Fujita M
  • Organizer: ADPD 2011
  • Place of Presentation: バルセロナ、スペイン
• [Presentation] Non-apoptotic cell death in hippocampus and cerebral cortex of bigenic mice overexpressing bothβsynuclein(P123H) andαsynuclein (2010)
  • Author(s): Fujita M., et al.
  • Organizer: BMB 2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Non-apoptotic cell death in hippocampus and cerebral cortex of bigenic mice overexpressing both β synuclein (P123H) and α synuclein. (2010)
  • Author(s): Fujita M
  • Organizer: BMB 2010
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2010-12-07
• [Presentation] βシヌクレイン(P123H)過剰発現型トランスジェニックマウスの解析 (2009)
  • Author(s): 藤田雅代, 他
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] βシヌクレイン(P123H)過剰発現による新規シヌクレイノパチーモデルマウスの確立 (2009)
  • Author(s): 藤田雅代, 他
  • Organizer: 第50回日本神経病理学会総会
  • Place of Presentation: 高松
  • Year and Date: 2009-06-04